losartan O-glucuronide | 138613-25-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: losartan O-glucuronide
• 英文别名: (2S,3S,4S,5R,6R)-6-[[2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
• CAS: 138613-25-9
• 化学式: C₂₈H₃₁ClN₆O₇
• 分子量: 599.043
• InChiKey: CIANECYYZOBTKQ-KGRBZTTASA-N

物化性质

• 沸点：
  885.4±75.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  42
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  189
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  洛沙坦 在 human liver microsomes 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 生成 氯沙坦N1-葡糖苷酸 、 losartan O-glucuronide 、 氯沙坦N2-葡糖苷酸
  参考文献：
  名称：

  The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan

  摘要：

  Losartan, candesartan, and zolarsartan are AT(1) receptor antagonists that inhibit the effect of angiotensin II. We have examined their glucuronidation by liver microsomes from several animals and by recombinant human UDP-glucuronosyltransferases (UGTs). Large differences in the production of different glucuronide regioisomers of the three sartans were observed among liver microsomes from human (HLM), rabbit, rat, pig, moose, and bovine. However, all the liver microsomes produced one or two N-glucuronides in which either N1 or N2 of the tetrazole ring were conjugated. O-Glucuronides were also detected, including acyl glucuronides of zolarsartan and candesartan. Examination of individual human UGTs of subfamilies 1A and 2B revealed that N-glucuronidation activity is widespread, along with variable regioselectivity with respect to the tetrazole nitrogens of these sartans. Interestingly, UGT1A3 exhibited a strong regioselectivity towards the N2 position of the tetrazole ring in all three sartans. Moreover, the tetrazole-N2 of zolarsartan was only conjugated by UGT1A3, whereas the tetrazole-N1 of this aglycone was accessible to other enzymes, including UGT1A5. Zolarsartan O-glucuronide was mainly produced by UGTs 1A10 and 2B7. UGT2B7, alongside UGT1A3, glucuronidated candesartan at the tetrazole-N2 position, whereas UGTs 1A7-1A10 mainly yielded candesartan O-glucuronide. in the case of losartan, no O-glucuronide was generated by any tested human enzyme. Nevertheless, UGTs 1A1, 1A3, 1A10, 2137, and 21317 glucuronidated losartan at the tetrazole-N2, while UGT1A10 also yielded the respective N1-glucuronide. Kinetic analyses revealed that the main contributors to losartan glucuronidation in HLM are UGT1A1 and UGT2B7. The results provide ample new data on substrate specificity in drug glucuronidation. (C) 2008 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2008.07.006

文献信息

• The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan
  作者：Anna Alonen、Moshe Finel、Risto Kostiainen

  DOI：10.1016/j.bcp.2008.07.006

  日期：2008.9

  Losartan, candesartan, and zolarsartan are AT(1) receptor antagonists that inhibit the effect of angiotensin II. We have examined their glucuronidation by liver microsomes from several animals and by recombinant human UDP-glucuronosyltransferases (UGTs). Large differences in the production of different glucuronide regioisomers of the three sartans were observed among liver microsomes from human (HLM), rabbit, rat, pig, moose, and bovine. However, all the liver microsomes produced one or two N-glucuronides in which either N1 or N2 of the tetrazole ring were conjugated. O-Glucuronides were also detected, including acyl glucuronides of zolarsartan and candesartan. Examination of individual human UGTs of subfamilies 1A and 2B revealed that N-glucuronidation activity is widespread, along with variable regioselectivity with respect to the tetrazole nitrogens of these sartans. Interestingly, UGT1A3 exhibited a strong regioselectivity towards the N2 position of the tetrazole ring in all three sartans. Moreover, the tetrazole-N2 of zolarsartan was only conjugated by UGT1A3, whereas the tetrazole-N1 of this aglycone was accessible to other enzymes, including UGT1A5. Zolarsartan O-glucuronide was mainly produced by UGTs 1A10 and 2B7. UGT2B7, alongside UGT1A3, glucuronidated candesartan at the tetrazole-N2 position, whereas UGTs 1A7-1A10 mainly yielded candesartan O-glucuronide. in the case of losartan, no O-glucuronide was generated by any tested human enzyme. Nevertheless, UGTs 1A1, 1A3, 1A10, 2137, and 21317 glucuronidated losartan at the tetrazole-N2, while UGT1A10 also yielded the respective N1-glucuronide. Kinetic analyses revealed that the main contributors to losartan glucuronidation in HLM are UGT1A1 and UGT2B7. The results provide ample new data on substrate specificity in drug glucuronidation. (C) 2008 Elsevier Inc. All rights reserved.